Classifications

• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
  • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
  • C12P17/10—Nitrogen as only ring hetero atom
  • C12P17/12—Nitrogen as only ring hetero atom containing a six-membered hetero ring

Definitions

• the invention relates to a new process for the production of nicotinamide.
• nitric acid oxidation of alkyl pyridines or the ammoxidation of alkyl pyridines (cf. Ullmann's Encyklopadie der Technische Chemie, 4th edition, vol. 23, p. 708 ff. Or vol. 19, P. 602 ff.).
• nitric acid oxidation especially of 2-methyl-5-ethylpyridine, is a very selective process, it contains a risk potential, for the minimization of which highly qualified personnel, optimal infrastructure and a high standard of know-how are essential.
• the task was therefore to develop an industrially applicable process that is based on the one hand on a relatively easy to control technology and on the other hand fulfills all criteria and requirements for an economical process.
• the first process step the production of 3-picoline from 2-methyl-1,5-diaminopentane, is described in detail in PCT application WO 94/22824.
• the resulting 3-picoline can be fed directly into the ammoxidation stage without intermediate cleaning.
• an intermediate purification for example by distillation, is preferably carried out, which has a positive influence on the catalyst life in the subsequent stage.
• the ammoxidation in the second stage is the subject of the PCT application PCT / EP 95/01945.
• a catalyst composition which consists of the oxides of vanadium, titanium, zircon and molybdenum in a molar ratio V 2 O 5 to TiO 2 to ZrO 2 of 1: 3: 4 to 1: 8: 16 and a MoO 3 - Content, based on V 2 O 5 , consists of 0.54% by weight to 1.20% by weight.
• Air is preferably used as the gas containing oxygen, since air has the advantage that the oxygen is already diluted with inert gases.
• the partial pressure of oxygen can be further regulated by adding inert gas such as nitrogen or oxygen-free process gases obtained by recycling.
• the reactants are 3-picoline, ammonia and oxygen-containing gas (calculated on O 2 ) gaseous in a molar ratio of 1: 1: 1.5 to 1: 8.5: 60 at 280 ° - 400 ° C, preferably at 310 ° - 380 ° C passed over the catalyst.
• the preferred molar composition of the feed gas is 3-picoline, ammonia and oxygen-containing gas (calculated on O 2 ) 1: 1: 1.5 to 1: 4:25.
• Water can have a favorable influence on the activity of the catalyst and is expediently passed over the catalyst with a molar ratio of 3-picoline between 0 and 5, preferably at about 1.5.
• the resulting 3-cyanopyridine can be in the form of an aqueous solution directly or after a work-up step, for. B. a crystallization, extraction or distillation of the biohydrolysis.
• a preferred work-up is the countercurrent extraction of 3-cyanopyridine with z. B. toluene and subsequent vacuum distillation.
• the solvent used, e.g. B. toluene, can be completely recycled.
• the biohydrolysis of 3-cyanopyridine as a substrate for nicotinamide is expediently carried out using microorganisms of the species Rhodococcus rhodochrous , Rhodococcus sp .
• S - 6 or Rhodococcus equi preferably with microorganisms of the species Rhodococcus sp .
• S - 6 (FERM BP-687), Rhodococcus rhodochrous J1 (FERM BP-1478) or with microorganisms of the species Rhodococcus equi TG328 (FERM BP-3791) *.
• the reaction is carried out using microorganisms of the species Rhodococcus rhodochrous (FERM BP-1478).
• S - 6, Rhodococcus rhodochrous J1 and Rhodococcus equi TG328 are microorganisms described in the literature.
• Rhodococcus rhodochrous J1 (FERM BP-1478) is described in EP-B 307 926, Rhodococcus sp .
• S-6 (FERM BP-687) in EP-A 0 188 316 and Rhodococcus equi TG328 (FERM BP-3791) in US Pat. No. 5,258,305 are described in detail.
• variants and mutants of these microorganisms are also suitable for the method.
• “Functionally equivalent variants and mutants” are understood to mean microorganisms which have essentially the same properties and functions as the original microorganisms. Such variants and mutants can happen to z. B. are formed by UV radiation.
• microorganisms are usually cultured (grown) in accordance with EP-B 307 926 before the actual biotransformation, and the active enzymes are induced.
• the biotransformation is preferably carried out using immobilized microorganism cells in a manner customary in the art.
• the biotransformation is expediently carried out in a pH range from 6 to 10, preferably in a pH range from 6.5 to 8.5.
• the pH is appropriately adjusted using a suitable phosphate buffer.
• the biotransformation can be carried out at a temperature of 5 to 50 ° C., preferably 15 to 30 ° C.
• Biohydrolysis of the 3-cyanopyridine which is expediently present in aqueous solution with a content of 5 to 30% by weight, is preferably carried out in a reactor cascade comprising 2 to 5 stirred reactors which are connected to one another and each contain the biocatalyst. Cascades with 3 to 4 agitators are particularly preferably used.
• the 3-cyanopyridine content in the aqueous solution is particularly advantageously between 10 and 20% by weight.
• the nicotinamide can be removed from the product stream e.g. B. can be obtained by crystallization.
• the reaction solution is preferably purified over activated carbon or a polystyrene resin (eg Amberlite) and the nicotinamide is isolated from the aqueous phase in a professional manner.
• This reactor contained 12 g of a dehydrogenation catalyst of the composition Pd + MgCl 2 on an Al 2 O 3 support (particle size: 0.32-1 mm). The reaction conditions were 280 ° C and about 1 bar. After a reaction time of 220 hours, the condensate from the dehydrogenation reactor contained 99.1% 3-picoline and 0.9% MPI (gas chromatography). A deactivation of the two catalysts over the reaction time was not observed.
• MPDA was evaporated and with a carrier gas flow of 15 ml / min H 2 at a pressure of approx . 1 bar and a reactor temperature of 320 ° C passed over the catalyst and cyclized to MPI.
• the MPDA used was a commercial product available from Du Pont de Nemours under the trade name Dytek A. The product from the cyclization reactor was kept in the gas phase and passed directly to a second reactor.
• This reactor contained 3 g of the dehydrogenation catalyst from Example 18 of WO 94/22 824 (particle size: 0.32-1 mm).
• the reactor temperature was 280 ° C, the pressure 1 bar.
• the educt was changed from MPDA to MPI and then to a raw material (3-MP raw), which consists of a mixture of the following composition: 74.9% MPI, 13.9% MPDA, 5.1% organic impurities (mainly methylcyclopentanediamine) and 6.1% water.
• the catalyst pretreated in this way was introduced in an amount of 60 cm 3 (82 g) into a tubular reactor (stainless steel, inside diameter 20 mm, length 1000 mm).
• 25.5 g of 3-picoline were passed over the catalyst over 10 hours.
• the turnover was 100%. 26.8 g of 3-cyanopyridine were obtained, corresponding to a yield of 95.0%.
• a quantity (72 kg, 53 liters) was filled in a tube reactor (stainless steel, inside diameter 21 mm, length 3000 mm, number of tubes 51).
• the molar composition of the feed gas was 3-picoline: O 2 : NH 3 1: 1.9: 1.5.
• 1,860 kg of 3-picoline were passed over the catalyst over 600 h. 1880 kg of 3-cyanopyridine were obtained, corresponding to a yield of 90.4%.
• Example 2b A quantity of the catalyst obtained from Example 2b (135 cm 3 , 160 g) was treated thermally at 620 ° C. for 6 h in an air stream. This was then filled into a tubular reactor (inner diameter 21 mm, length 1000 mm). At a catalyst bed temperature of 375 ° C, a mixture of 3-picoline, air, nitrogen and ammonia was passed over the catalyst. The feed rate was 3-picoline 11 gh -1 , (corresponds to 81 g picoline per liter catalyst per h), air 30 1h -1 , nitrogen 285 lh -1 , ammonia 4 gh -1 , a molar ratio corresponding to 3-picoline: O 2 : NH 3 1: 2: 2.6.
• a granulate with a dimension between 3-4 mm was formed from the catalyst obtained in Example 2b.
• a quantity (1 liter, 1.50 kg) was placed in a tubular reactor (stainless steel, inside diameter 21 mm, length 3000 mm).
• a mixture of 3-picoline, air, nitrogen and ammonia was at a catalyst bed temperature of Passed 353 ° C over the catalyst.
• the feed rate was 3-picoline 96 gh -1 (corresponds to 96 g picoline per liter catalyst per h), air 210 1h -1 , nitrogen 1340 lh -1 , ammonia 60 gh -1 .
• 2305 g of 3-picoline were passed over the catalyst bed over 24 h.
• 2380 g of 3-cyanopyridine were obtained, corresponding to a yield of 90%.
• the 3-picoline conversion was 97.5%.
• a solution of 10% 3-cyanopyridine was converted to NSA.
• cyanopyridine was converted quantitatively to NSA, the first reactor containing 45 g of immobilized microorganisms (dry weight) and the two further reactors each containing 7.5 g (dry weight) of immobilized microorganisms.
• the biocatalyst remained in the respective reactors throughout the experiment.
• the biocatalyst contained immobilized microorganisms of the species Rhodococcus rhodochrous J1.
• the reaction took place at a temperature of 25 ⁇ 1 ° C and a pH of 8 to 8.5.
• the pH was adjusted using phosphoric acid and sodium hydroxide solution.
• the conversion of cyanopyridine ran for 2400 h without the product stream containing more than 0.05% cyanopyridine, which corresponds to a conversion of> 99.5%.
• the activity of the catalyst was exhausted after this time.
• a solution of 15% 3-cyanopyridine was converted to NSA.
• cyanopyridine was converted quantitatively to NSA, the first reactor containing 6 kg of immobilized microorganisms (dry weight) and the two further reactors each containing 0.9 kg (dry weight) of immobilized microorganisms.
• the biocatalyst remained in the respective reactors throughout the experiment.
• the biocatalyst contained immobilized microorganisms of the species Rhodococcus rhodochrous J1.
• the reaction took place at a temperature of 24 ⁇ 2 ° C and a pH of 7 to 8.5.
• the pH was adjusted using phosphoric acid and sodium hydroxide solution, potassium dihydrogen phosphate also being used for buffering (1-3 mg / l).
• NSA solution was then filtered continuously.
• a three-stage filtration system was used. The product solution was first fed to a GAF filter (10 - 30 ⁇ m pore size), then to a sterile filter (pore size 0.2 ⁇ m) and finally to ultrafiltration (pore size from 10,000 to 30,000 Daltons).
• the filtered product solution was concentrated in a falling film evaporator to 60 to 80% NSA. Water removed from the product could be recycled in the biohydrolysis.
• the product isolation was carried out in a spray dryer with an integrated fluidized bed (fluidized spray dryer).
• the NSA content in the product obtained was> 99.7% (titration) and corresponded to pharmaceutical quality.

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• 1996
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